Mitochondrial redox imbalance and decreased antioxidant defense-a decline in a cell's ability to maintain homeostasis between free radicals generated from cellular respiration and enzymatic free radical detoxification-may accompany altered cortical circuit organization and function in patients with neuropsychiatric disorders. However, it is unknown if decreased antioxidant defense and reactive oxygen species accumulation (ROS) during development of cortical circuits contributes to aberrant circuit formation and its consequences. Patients with 22q11 deletion syndrome (22q11DS) are more susceptible to psychiatric disorders than the rest of the population; therefore, 22q11DS has been suggested as a model for studying the neurodevelopmental origins of neuropsychiatric disorders. About one quarter of the genes located in the commonly deleted region in the 22q11DS encode proteins that localize to mitochondria. I propose to characterize changes in the developmental capacity of cortical neurons that develop due to altered mitochondrial function in mouse models of 22q11DS and determine how these changes could compromise circuit formation. Among 22q11 mitochondrial genes, thioredoxin reductase (TxnRd2), maximally expressed during cortical circuit differentiation, encodes a primary mitochondrial H2O2 scavenger. Thus, I will investigate how disrupted scavenging activity of TxnRd2 impacts mitochondrial antioxidant defense and alters cortical neuron development. I will test the hypothesis that diminished mitochondrial antioxidant defense during late stages of neuronal development, due to diminished dosage of TxnRd2, disrupts the capacity of cortical neurons to establish optimal connections. To test this hypothesis, an allelic series of TxnRd2 mutations will be generated specifically in developing cortical projection neurons, using an inducible Cre-recombinase system (Cux2GFP-Cre). Integrity of neuronal growth, differentiation and organelle distribution will be analyzed to evaluate changes in the capacity of cortical neurons to engage in normal circuit development. ROS metabolism will be further manipulated in TxnRd2-depleted neurons to link antioxidant defense to the capacity of individual neurons to build circuits. My studies will define the effects of mitochondrial accumulation of ROS due to diminished antioxidant defense on neuronal integrity, and will establish the role of altered pyramidal neuron differentiation in the formation of circuits in 22q11DS. A homogenous population of neurons with genetically controlled enzymatic antioxidant defense permit comparison of regulation of redox balance in cells with equal metabolic demand, and analysis of altered neuronal capacity for optimal cortical circuit development. My data will establish a role for antioxidant defense in the capacity of individual neurons to build circuits and will provide insight into the role of redox imbalance in aberrant circuit connectivity in a wide range of behavioral disorders.